Research Article: Opiate Sensitization Induces FosB/ΔFosB Expression in Prefrontal Cortical, Striatal and Amygdala Brain Regions

Date Published: August 23, 2011

Publisher: Public Library of Science

Author(s): Gary B. Kaplan, Kimberly A. Leite-Morris, WenYing Fan, Angela J. Young, Marsha D. Guy, Pranela Rameshwar. http://doi.org/10.1371/journal.pone.0023574

Abstract: Sensitization to the effects of drugs of abuse and associated stimuli contributes to drug craving, compulsive drug use, and relapse in addiction. Repeated opiate exposure produces behavioral sensitization that is hypothesized to result from neural plasticity in specific limbic, striatal and cortical systems. ΔFosB and FosB are members of the Fos family of transcription factors that are implicated in neural plasticity in addiction. This study examined the effects of intermittent morphine treatment, associated with motor sensitization, on FosB/ΔFosB levels using quantitative immunohistochemistry. Motor sensitization was tested in C57BL/6 mice that received six intermittent pre-treatments (on days 1, 3, 5, 8, 10, 12) with either subcutaneous morphine (10 mg/kg) or saline followed by a challenge injection of morphine or saline on day 16. Mice receiving repeated morphine injections demonstrated significant increases in locomotor activity on days 8, 10, and 12 of treatment (vs. day 1), consistent with development of locomotor sensitization. A morphine challenge on day 16 significantly increased locomotor activity of saline pre-treated mice and produced even larger increases in motor activity in the morphine pre-treated mice, consistent with the expression of opiate sensitization. Intermittent morphine pre-treatment on these six pre-treatment days produced a significant induction of FosB/ΔFosB, measured on day 16, in multiple brain regions including prelimbic (PL) and infralimbic (IL) cortex, nucleus accumbens (NAc) core, dorsomedial caudate-putamen (CPU), basolateral amygdala (BLA) and central nucleus of the amygdala (CNA) but not in a motor cortex control region. Opiate induced sensitization may develop via Fos/ΔFosB plasticity in motivational pathways (NAc), motor outputs (CPU), and associative learning (PL, IL, BLA) and stress pathways (CNA).

Partial Text: Sensitization is an addiction-related phenomenon that produces enduring enhancement of behavioral or locomotor responses after repeated and intermittent administration of psychostimulants and opiates [1]. Extensive investigations have shown that the repeated administration of psychostimulants such as cocaine, amphetamine, and nicotine result in persistent motor and neurochemical sensitization in animal models [2], [3]. Sensitization to drugs of abuse and associated stimuli is hypothesized to occur via plasticity in motor, motivational and cognitive neural systems and is thought to contribute to drug craving and relapse in addiction. Sensitization develops to the stimulant effects of opiates [4], [5] and to their conditioned rewarding properties, as measured by conditioned place preference [6], [7]. Sensitization develops to the conditioned aversive effects of withdrawal after repeated drug administration [8]. Thus, addiction can be viewed as a progressive phenomenon resulting partly from the sensitization of the stimulant and rewarding effects of drugs and from the conditioned aversive properties of drug withdrawal. Sensitization can last for days, weeks or months after cessation of drug exposure and is thought to contribute to relapse in addiction [9].

Figure 1 illustrates the motor effects of intermittent morphine administration given on days 1, 3, 5, 8, 10, and 12 of pre-treatment, as measured by the total distance traveled over 180 min. A two-way ANOVA demonstrated significant effects of treatment (vehicle vs. morphine) group (F1, 232 = 235.4; P<0.0001), treatment day (F5, 232 = 3.47; P<0.01) and treatment group×day interaction (F5, 232 = 3.39; P<0.0001). Post-hoc testing revealed that on days 8, 10, and 12 of treatment, the morphine treatment groups showed significant differences in locomotor responses compared with day 1 of treatment. Thus, repeated morphine pre-treatment produced increasing motor stimulant effects within four to six treatments resulting in the development of locomotor sensitization in this model. In summary, repeated and intermittent morphine injections produced progressive increases in motor activity. In morphine pre-treated mice, a morphine injection on challenge day (day 16) produced more than a two-fold increase in locomotor behavior compared to vehicle pre-treated mice (receiving the same morphine challenge). Morphine sensitized mice demonstrated associated increases in FosB/ΔFosB immunoreactivity in PL, IL, NAcC, NAcS, CPU, CNA, and BLA regions. Source: http://doi.org/10.1371/journal.pone.0023574